Psoriasis is a lifelong skin disease that occurs when faulty signals in the immune system cause skin cells to regenerate too quickly, on the order of every three to four days instead of the usual 30-day cycle. Extra skin cells build up on the skin's surface, forming red, flaky, scaly lesions that can itch, crack, bleed and be extremely painful. Psoriasis generally involves the joints, limbs and scalp but it can appear anywhere on the body, covering some people from head to toe. More than 7 million Americans have been diagnosed with psoriasis and/or psoriatic arthritis, a degenerative disease of the joints and connective tissues associated with psoriasis. Psoriasis typically first strikes people between the ages of 15 and 35, but can affect anyone at any age, including children.
Psoriasis is characterized by erythematous eruptions, often in papules or plaques, and usually having a white, silvery scale. Psoriasis is generally considered an inflammatory skin condition. Other inflammatory skin conditions include atopic dermatitis (eczema), seborrhoeic dermatitis, rosacea, acne, as well as contact dermatitis (typically arising from allergic reaction to poison ivy and other allergens).
Psoriasis is persistent and unpredictable in its course. The exact etiology of psoriasis is unknown. It is postulated that psoriasis may involve abnormalities in essential fatty acid metabolism, free radical generation, lipid peroxidation, and/or release of lymphokines. One study showed that lipid peroxidation mediated by free radicals is one of the important causes of cell membrane destruction and cell damage associated with psoriasis. Tekin N. S., Accumulation of oxidized low-density lipoprotein in psoriatic skin and changes of plasma lipid levels in psoriatic patients, Mediators Inflamm. 12, 78454 (2007). Other studies also reported that oxidative stress and increased free-radical generation link to psoriasis. Rashmi R, Clin. Exp. Dermatol. 34, 658-63 (2009); Cooke, M. S., Oxidative DNA damage: mechanisms, mutation, and disease, the FASEB Journal, 17, 1195-1214 (2003).
Despite a voluminous scientific literature and numerous treatment strategies, there is still no effective treatment for psoriasis that is completely without side effects. Conventional therapeutic regimens for psoriasis include topical or intralesional application of corticosteroids, anthralin, tazarotene (a retinoid), acitretin (a second-generation retinoid), calcipotriene (vitamin D3) and/or zinc compounds, and/or selenium compounds, and/or coal tar compounds; or various light therapies; or an oral or injected systemic agent. No single therapy is ideal, and it is rare for a patient not to be treated with several alternatives during the relapsing and remitting course of the disease. Whereas systematic treatment can induce prompt resolution of psoriatic lesions, suppression often requires ever-increasing doses, sometimes with toxic side effects, and tapering of therapy may result in rebound phenomena with extensions of lesions, possibly to exfoliation. Other inflammatory skin conditions are typically treated with the same types of therapies.
As set forth in more detail hereafter, the present invention is based on the topical use of nitrone spin trap compositions as a treatment for psoriasis and other inflammatory skin conditions.
Nitrone spin traps are potent free radical scavengers and antioxidants, and are commonly used as analytical tools to study free radicals. Nitrones behave as spin trapping agents when a diamagnetic nitrone compound (the “spin trap”) reacts with a transient free radical species (having the “spin”) to provide a relatively more stable radical species (referred to as the “spin adduct”). The spin adduct may be detectable by electron paramagnetic resonance (EPR) spectroscopy, or electron spin resonance (ESR) if the spin adduct has a reasonable lifetime. Thus, spin trapping allows previously unobservable free radicals to be identified and studied using ESR, EPR, and related techniques. Sudha Rana, Electron paramagnetic resonance spectroscopy in radiation research: Current status and perspectives, J. Pharmacy & BioAllied Sciences, 2, 80-87 (2010).
The use of nitrones as spin traps for studying unstable free radicals has been applied to biological systems. In this regard, α-phenyl t-butyl nitrone (PBN), 5,5-dimethylpyrroline N-oxide (DMPO) and related compounds have been used to identify superoxide (O2.) and hydroxyl radicals (HO.) in biological systems. Additionally, such nitrones have been used to study lipid peroxidation and other free radical-induced biological processes.
Besides serving as research aids or diagnostic tools, nitrone spin traps are extremely therapeutic. For example, PBN and derivatives thereof, have been reported for the treatment of a wide variety of disease conditions arising from or characterized by free radical-induced oxidative damage. Such disease conditions include, for example, disorders of the central nervous system (CNS) and the peripheral nervous system, such as stroke, Parkinsonism, traumatic nerve damage and the like, and disorders of the peripheral organs, such as atherosclerosis, cardiac infarction, ulcerative colitis and the like. Nitrones have also been reported to treat certain inflammatory conditions, such as arthritis.
It would be desirable to have an effective treatment for psoriasis, particularly via a topical administration of an efficient free radical scavenger such as nitrone spin traps.
To be an effective topical therapeutic agent for treating psoriasis, it is desirable to be able to administer the nitrone spin traps at high doses, especially initially, to the localized area surrounding the psoriasis plague, to minimize the amount of free radical-induced oxidative damage that occurs. Thus, the nitrone spin traps used to treat psoriasis conditions should be non-toxic or have very low toxicity.
It is also important that the nitrone spin traps have sufficient solubility at the biological site where the free radicals are generated so that the radicals are trapped by the nitrone spin traps before they are quenched or cause oxidative damage by their surroundings. Thus, it would be particularly desirable to be able to optimize the solubility of the nitrone spin traps from aqueous to lipophilic.
It is further desirable that the nitrone spin traps either be stable per se or have the ability to be stabilized in admixture with other components, so that preparations can be marketed with a suitably long shelf-life and such that prolonged activity can be obtained once topical application has been made.
Accordingly, a need exists for nitrone spin traps having low toxicity, increased solubility, and long shelf-life for the effective topical treatment of psoriasis.